Obesity has risen dramatically over the last 30 years. In the US alone, 60 million people are defined as clinically obese. Juonala, et al., “Childhood Adiposity, Adult Adiposity, and Cardiovascular Risk Factors,” N Engl J Med 365(20):1876-85 (2011). Especially concerning is the almost epidemic rate of childhood obesity. Ludwig, D. S., “Childhood Obesity—the Shape of Things to Come,” N Engl J Med 357(23):2325-7 (2007). Obesity can cause or contribute to many health problems such as type-2 diabetes, cardiovascular disease, asthma, and cancer. Of further importance is the fact that many human tissues can become fatty and lose function as a consequence of disease or insult. Examples of this include liver cirrhosis from infection or excess alcohol consumption. Others include conversion of healthy red bone marrow to fatty yellow marrow by mesenchymal stem cells as a consequence of age and also of osteoporosis. Current medications, most small molecules, target appetite, nutrient and food absorption, and increasing metabolism. These drugs have undesirable side effects. In addition, surgical methods are invasive and have associated risks of infection and tissue damage. Hormone or soluble peptide therapeutics for obesity are severely lacking and there is a great need for new therapeutics to control excess fat deposition.
While no single factor appears to be responsible for the dangerous rise in obesity rates, several focal points are ascribed to being causal: genetics, behavior, food intake, stress and lack of exercise. One factor now beginning to be uncovered is early life exposures (The Barker Theory on the developmental origins of health and disease) to environmental contaminants that appear to “reprogram” human physiology. Trosko et al., “Factors to Consider in the Use of Stem Cells for Pharmaceutic Drug Development and for Chemical Safety Assessment,” Toxicology 270(1):18-34 (2010). Environmental compounds termed obesogens have been identified that disrupt the endocrine system and cause increased adipogenesis in both in vitro and in vivo models. Janesick, et al., “Endocrine Disrupting Chemicals and the Developmental Programming of Adipogenesis and Obesity,” Birth Defects Res C Embryo Today 93(1):34-50 (2011); Grun et al., “Environmental Obesogens: Organotins and Endocrine Disruption Via Nuclear Receptor Signaling,” Endocrinology 147(6 Suppl):550-5 (2006). Recently tributlytin (TBT) and tetrabromobisphenol-A (TBBPA) have been reported to increase adipogenesis at least in part by serving as ligands for the transcription factor peroxisome proliferator activated receptor gamma (PPARγ). Other compounds reported to increase obesity rates such as bisphenol A (BPA) and dichlorodiphenyl-dichloroethylene (DDE), the major metabolite of the pesticide DDT, do not appear to be ligands of PPARγ suggesting that obesogens may have additional effects on adipogenesis and multipotent stem cell function. Grun et al., “Environmental Obesogens: Organotins and Endocrine Disruption Via Nuclear Receptor Signaling,” Endocrinology 147(6 Suppl):550-5 (2006); Janesick et al., “Obesogens, Stem Cells and the Developmental Programming of Obesity,” Int J Androl 35(3):437-48 (2012). Thus, a major knowledge gap is how obesogens act as environmental signals to alter the fate of MSCs by increasing differentiation into the adipocyte lineage. While obesogens are currently defined by their ability to increase adipogenesis, they also influence MSC and whole organism fate long after exposure and additionally may influence several generations of offspring. Developmental exposure to obesogens (in utero or neonatal) may have a profound effect on MSC fate, adipogenesis, and obesity throughout life. Epidemiological studies have provided evidence that early and prenatal exposure to environmental factors including BPA and DDE influence the adult risk of developing cancer and obesity. Boekelheide et al., “Predicting Later-Life Outcomes of Early-Life Exposures,” Environ Health Perspect 120(10):1353-61 (2012). Given the dire rise in obesity, studies on obesogen exposure are urgently needed.
Another condition involving adipogenesis is thyroid eye disease (TED). TED is a disfiguring and sight-threatening autoimmune disease that involves inflammation of the orbit. TED has perplexed clinicians and scientists for decades. The increased scarring, especially of the extraocular muscles, and hyaluronan deposition along with substantial fat accumulation leads to protrusion of the eye (exophthalmos) and optic nerve compression. Bahn, R. S., “Graves' Ophthalmopathy,” N Engl J Med 362(8):726-38 (2010); Kuriyan et al., “The Eye and Thyroid Disease,” Curr Opin Ophthalmol 19(6):499-506 (2008). Why TED is manifested in nearly half of patients with Graves' hyperthyroidism, and with differing levels of severity or progression, remains unclear and are intriguing research questions requiring active investigation. To date, there is no effective treatment to prevent the destructive increase in orbital tissue. Bahn, R. S., “Graves' Ophthalmopathy,” N Engl J Med 362(8):726-38 (2010). Furthermore, beyond supportive treatment and surgical procedures such as lid reconstruction, alleviation of muscle restriction, and orbital decompression, there is no reliable method to reverse or improve the debilitating outcomes of TED.
The present invention is directed to overcoming these and other deficiencies in the art.